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Obese NHP Resource

To develop opportunities for research in the field of nonhuman primate metabolism, Dr. Paul Kievit and his colleagues have established two colonies of macaques that are fed a diet high in saturated fat, simple carbohydrates and cholesterol. These Diet-Induced Obesity (DIO) nonhuman primate (NHP) models are maintained in an effort to understand the progression of obesity and its associated metabolic disorders, as well as to provide a model for treating these disorders. Briefly, the two models are:

1. DIO Rhesus macaques (Macaca mulatta). These studies involve singly- or group-housed animals that have extensive phenotypic characterization, including glucose tolerance, insulin tolerance, food intake, energy expenditure, activity, and cardiovascular function. These macaques have been used in a variety of studies, including investigation of cardiovascular changes in response to a high-fat diet, as well as pharmaceutical and surgical therapeutics for obesity.

2. DIO in Cynomolgus macaques (Macaca fascicularis). This cohort of over 30 cynomolgus macaques are maintained on a high-fat/high-calorie diet. These animals can support research models that investigate metabolic disease in NHP. As part of the Obese NHP Resource, these animals have extensive phenotypic characterization, including glucose tolerance, insulin tolerance, body composition, and food intake.

This resource is being expanded for internal and external studies. The primary goals for the Obese NHP Resource are:

To encourage interdisciplinary, collaborative studies that will specifically lead to additional funding in the various metabolic disease areas. This will be accomplished through interaction with the Division of Cardiometabolic Health.

To understand the timeline for the progression of the different aspects of the metabolic disease;i.e., obesity, diabetes, cardiovascular disease, and immune dysfunction.

To determine the characteristics (i.e., genetic and behavioral) that make some animals susceptible to diet induced obesity, while other animals are highly resistant.

Provide oversight and coordination of all internal and external research projects, including promotion of collaborative efforts.

Provide investigators with a Bio-bank of harvested samples from animals at various stages of obesity. Samples include serum, plasma, and specific tissue samples collected during the development of obesity.

Technical approaches employed by the Resource:

Magnetic resonance spectroscopy (MRS). The ONPRC has recently obtained a 3T magnet from the main OHSU campus. One of the possible applications of this technology to the Obese NHP resource is through MRS analysis of ectopic lipid accumulation in the liver and muscle (as well as other tissues). This has become a valuable and powerful technique used in humans to investigate fatty liver disease and the correlation of ectopic lipid accumulation with insulin resistance and the progression to diabetes.

Dual energy X-ray analysis (DEXA). The ONPRC has a Hologic Discovery A DEXA scanner for doing body composition analysis. This is the same machine used in OHSU clinics. This machine is available through charge-backs ($50 per animal), which covers its maintenance contract and upgrades.

Ex vivo islet culture system. A large-capacity physiological culture system has been recently established that enables the analysis of cells and organelles such as pancreatic islets under conditions that approximate in vivo conditions of CO2, O2, temperature, and 3-dimensional suspension culture. This system is optimized for NHP islets, and includes detailed analysis of islet function utilizing perifusion.

Energy expenditure. Double-labeled water analysis is commonly used in humans (children and adults) to measure basal energy expenditure. This technique has been validated in NHPs as well. This is a non-invasive technique that relies on two forms of labeled water (H218O and 2H2O) and the utilization of these substrates to generate CO2. This is a valuable technique to use in NHPs because it can be performed on large numbers of animals, which makes it ideal for both individually-housed animals as well as group-housed animals. The Obese NHP Resource also has access to an Oxymax system from Columbus Instruments to measure indirect calorimetry and energy expenditure. This system was specifically designed for the use of NHP.

Telemetry systems. Telemetry systems that measure blood pressure, heart rate, activity, body temperature, and ECG are employed for individually housed animals, and Actiwatch accelerometers can be used in both single and group-housed animals.

Hyperinsulinemic-euglycemic clamps. This is an important technique for extensive analysis of insulin resistance. While glucose and insulin tolerance tests (both used extensively at ONPRC) can give an indirect measure of whole-animal insulin resistance, clamp studies are used to detect insulin resistance in peripheral tissues (i.e., muscle and fat). These studies use the infusion of labeled substrates while clamping insulin at high levels and infusing glucose to maintain euglycemia.

Contrast-enhanced ultrasound (CEU). This is a technique to measure vascular reactivity and tissue perfusion. This non-invasive perfusion imaging technique relies on the ultrasound detection of microbubble contrast agents during their tissue microvascular transit. Encapsulated microbubble contrast agents that are currently used for CEU imaging are ideal for the assessment of perfusion, since they are inert and remain in the vascular compartment, and their microvascular rheology is similar to that of red blood cells.

Immune function. Through Pathobiology and VGTI investigators, there is vast array of expertise to study NHP immune function. It is well accepted that obesity and diabetes in humans is associated with immune disorders and inflammation, and that this condition may contribute to the progression of the disease and the pathology.